Regulators of the cell cycle have gained widespread importance in proliferative diseases. Cyclin-dependent kinases (CDKs) are a family of enzymes which become activated in specific phases of the cell cycle.
A wide variety of diseases are characterized by uncontrolled cell proliferation that results from some fault in the regulatory pathways in the cell cycle [e.g. overexpression of cyclins or deletions of genes encoding CKIs (CDK inhibitory proteins)]. The overexpression of cyclinD1 leads to the deregulation of CDK4-D1 kinase activity and thereby contributes to uncontrolled cell proliferation. With knowledge of the role of CDKs in cell cycle regulation and the discovery that approximately 90% of all neoplasias are associated with CDK hyperactivation leading to the inactivation of the Rb pathway, CDKs are attractive targets for the development of anti-tumor drugs.
The prominent role of CDK/cyclin kinase complexes, in particular CDK4/cyclin D1 kinase complexes, in the induction of cell proliferation and their deregulation in tumors, makes them ideal targets for developing highly specific anti-proliferative agents.
Flavopiridol and its analogs are well known as effective CDK inhibitors and offer a potential approach to anti-proliferative therapy.
The applicant's co-pending published US Patent application no. 2004/0106581 describes novel compounds useful in inhibiting CDKs and having good selectivity and cytotoxicity against various proliferative cell lines. This patent application is incorporated herein by reference in its entirety. The novel compounds disclosed in the aforesaid patent application, have two chiral centers and hence, can exist as four enantiomers i.e. (+)-trans, (−)-trans, (+)-cis and (−)-cis.
It is well known in the art that the enantiomers of a given chemical compound, despite sharing identical chemical composition, can have very different actions when placed in biological systems. It is often the case that one enantiomer provide the beneficial effects while the opposite enantiomer may be deleterious or inert. Thus, advantages associated with the administration of the racemic mixture may be retained by using a single enantiomer of the compound without associated adverse side effects.
The studies specifically establish that the CDK inhibitory activity and the anti-proliferative activity is due to the (+)-trans enantiomer of pyrrolidines substituted with flavones represented by formula (I) rather than the (−)-trans enantiomer.
It would be desirable for the (+)-trans enantiomer of pyrrolidines substituted with flavones, the compounds of formula (I), to be available in a form substantially free of its (−)-trans enantiomer to provide a safe and an effective method for the treatment of diseases or disorders mediated by inhibition of cyclin dependant kinases (CDKs) and also for the treatment of diseases associated with excessive cell proliferation such as cancer.
In view of this finding, the present inventors have developed a new process for the preparation of an enantiomerically pure (+)-trans enantiomer of pyrrolidines substituted with flavones represented by formula (I).